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Powrózek T, Otieno MO, Maffeo D, Frullanti E, Martinez-Useros J. Blood circulating miRNAs as pancreatic cancer biomarkers: An evidence from pooled analysis and bioinformatics study. Int J Biol Macromol 2025; 308:142469. [PMID: 40180095 DOI: 10.1016/j.ijbiomac.2025.142469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 03/09/2025] [Accepted: 03/22/2025] [Indexed: 04/05/2025]
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers, characterized by a poor prognosis. Currently, there are no screening programs for the early detection of PC, and existing diagnostic methods are primarily limited to high-risk individuals. Biomarkers such as CA19-9 have not significantly improved early diagnosis, making the identification of new potential biomarkers crucial for routine clinical practice. Among the candidate biomarkers, miRNAs have been most extensively studied due to their role in regulating gene expression (either as oncomiRs or tumor suppressor miRNAs) and their potential for minimally invasive analysis through liquid biopsy techniques. This review aims to summarize the current literature on blood-circulating miRNAs and their diagnostic value in PC detection, considering the context of CA19-9 and benign pancreatic diseases. The data from the collected studies were curated through both statistical and bioinformatics analyses to identify the most promising miRNAs with optimal diagnostic accuracy for PC detection and to assess their role in the molecular processes leading to tumor development.
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Affiliation(s)
- Tomasz Powrózek
- Department of Human Physiology, Medical University of Lublin, Lublin, Poland.
| | - Michael Ochieng' Otieno
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, Madrid, Spain
| | - Debora Maffeo
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Elisa Frullanti
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Javier Martinez-Useros
- Translational Oncology Division, Oncohealth Institute, Fundacion Jiménez Díaz University Hospital, Madrid, Spain; Area of Physiology, Department of Basic Health Sciences, Faculty of Health Sciences, Rey Juan Carlos University, Madrid, Spain
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Hipler NM, Thon C, Lehr K, Furnari M, Obst W, Keitel V, Weigt J, Link A. Exploring microRNAs in Bile Duct Stents as Diagnostic Biomarkers for Biliary Pathologies. Cancers (Basel) 2025; 17:1171. [PMID: 40227700 PMCID: PMC11987880 DOI: 10.3390/cancers17071171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/24/2025] [Accepted: 03/27/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Obstruction of the biliary duct may be caused by various conditions ranging from chronic inflammation to neoplasia, including cholangiocarcinoma (CCA). While the definite histological diagnosis of intrahepatic lesions is relatively straightforward, the diagnostic workup of biliary duct stenosis can be challenging, despite the availability of novel tools for intraductal diagnosis. This proof-of-principle study aimed to investigate whether microRNAs (miRNAs) from bile duct stents may be used as biomarkers to differentiate between various bile duct diseases. METHODS For this purpose, we included 100 patients with one or more bile duct stents for various reasons, including malignant disease (n = 40), stenosis due to liver transplantation or surgery (n = 60), and cholangitis (n = 42). During endoscopic retrograde cholangiography, the stents were collected, and miRNA analyses were performed to evaluate miR-16, miR-21, and miR-223. RESULTS All studied miRNAs were successfully detected from the specimens obtained from the bile duct stents and were comparable in different stents from the same subjects. Following normalization, significant increases in miR-16, -21, and -223 levels were identified in patients with cholangitis compared to specimens from a non-inflammatory cohort. However, when comparing the data from patients in the malignant and non-malignant cohorts, the individual levels of miR-16, miR-21, and miR-223 showed high variation, without reaching a statistically significant difference. CONCLUSIONS In summary, bile duct stents can be considered as potential sources of intraductal biomarkers, specifically miRNAs. Further profiling and validation analyses are necessary to identify the most appropriate miRNA targets for differentiating bile duct diseases.
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Affiliation(s)
- Noam Mathias Hipler
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Konrad Lehr
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Manuele Furnari
- Gastroenterology Unit, Department of Internal Medicine, Policlinico San Martino-IRCCS Hospital, University of Genoa, 16145 Genoa, Italy;
| | - Wilfried Obst
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Jochen Weigt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; (N.M.H.); (C.T.); (K.L.); (W.O.); (V.K.); (J.W.)
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Gasparello J, Ceccon C, Angerilli V, Comunello T, Sabbadin M, D'Almeida Costa F, Antico A, Luchini C, Parente P, Bergamo F, Lonardi S, Fassan M. Liquid biopsy in gastric cancer: A snapshot of the current state of the art. THE JOURNAL OF LIQUID BIOPSY 2025; 7:100288. [PMID: 40027230 PMCID: PMC11863821 DOI: 10.1016/j.jlb.2025.100288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Circulating tumor DNA (ctDNA) is nowadays considered a robust source to search for druggable tumoral genetic alterations, and in some specific settings liquid biopsy (LB) is already part of the diagnostics scenario and it has successfully implemented in the everyday practice. Three strengths make LB an extraordinary tool: i) to represent the complex molecular mosaicism that characterizes spatially heterogeneous malignancies; ii) to monitor in real-time the tumoral molecular landscape (i.e. to depict the longitudinal/temporal tumor evolution); iii) to ensure molecular profiling even in those cases in which tissue sampling is not feasible or not adequate. This review provides a snapshot of the current state of the art concerning ctDNA assay utility in gastric cancer (GC), testing its robustness as marker and seeking to understand the reasons for the delay in its application in clinical practice.
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Affiliation(s)
| | - Carlotta Ceccon
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Pathology, Nijmegen, the Netherlands
| | - Tatiane Comunello
- Department of Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil
| | - Marianna Sabbadin
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Antonio Antico
- Department of Clinical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | | | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
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Wang Z, Wu Q. Advancements in non-invasive diagnosis of gastric cancer. World J Gastroenterol 2025; 31:101886. [PMID: 39958452 PMCID: PMC11752698 DOI: 10.3748/wjg.v31.i6.101886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 12/08/2024] [Accepted: 12/20/2024] [Indexed: 01/10/2025] Open
Abstract
Gastric cancer (GC), a multifaceted and highly aggressive malignancy, represents challenging healthcare burdens globally, with a high incidence and mortality rate. Although endoscopy, combined with histological examination, is the gold standard for GC diagnosis, its high cost, invasiveness, and specialized requirements hinder widespread use for screening. With the emergence of innovative technologies such as advanced imaging, liquid biopsy, and breath tests, the landscape of GC diagnosis is poised for radical transformation, becoming more accessible, less invasive, and more efficient. As the non-invasive diagnostic techniques continue to advance and undergo rigorous clinical validation, they hold the promise of significantly impacting patient outcomes, ultimately leading to better treatment results and improved quality of life for patients with GC.
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Affiliation(s)
- Zhen Wang
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Qi Wu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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Koopaie M, Arian-Kia S, Manifar S, Fatahzadeh M, Kolahdooz S, Davoudi M. Expression of Salivary miRNAs, Clinical, and Demographic Features in the Early Detection of Gastric Cancer: A Statistical and Machine Learning Analysis. J Gastrointest Cancer 2024; 56:15. [PMID: 39520622 DOI: 10.1007/s12029-024-01136-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE Gastric cancer ranks as one of the top five deadliest cancers worldwide and is often diagnosed at late stages. Analysis of saliva may provide a non-invasive approach for detection of malignancies in organs associated with the oral cavity. This research aims to analyze salivary microRNA expression together with clinical and demographic features with the aim of diagnosing gastric cancer. MATERIALS The study included 19 patients with early-stage gastric cancer and 19 healthy controls. Saliva samples were collected and processed for RNA isolation. Salivary expression of miR-223-3p and miR-21-5p were measured using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Receiver operating characteristic (ROC) curves were generated to evaluate the accuracy of diagnostic models. Machine learning algorithms, multiple logistic regression, and principal component analysis (PCA) were used to assess the predictive power of miRNAs in conjunction with clinical-demographic features. RESULTS Significant upregulation of miR-223-3p and downregulation of miR-21-5p in saliva were observed in patients with gastric cancer. The area under ROC curve (AUC) values for salivary miR-21-5p, salivary miR-223-3p, and their multiple logistic regression were determined to be 0.723, 0.791, and 0.850, respectively. The AUC for multiple logistic regression model was 0.919. The PCA model led to the highest diagnostic odds ratio (DOR) of 134.33 (sensitivity = 0.785, specificity = 1.00, AUC = 903). Application of machine learning methods, and in particular a random forest algorithm, showed high accuracy in diagnosing patients with gastric cancer (sensitivity = 1.00, specificity = 0.857, AUC = 0.93). CONCLUSION The application of validated salivary diagnostics in clinical practice could help facilitate earlier diagnosis of gastric cancer and improve medical outcome. Expression of miR-21 and miR-223-3p in saliva together with clinical and demographic features, appears promising in screening for GC.
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Affiliation(s)
- Maryam Koopaie
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, North Kargar St, P.O.BOX:14395-433, Po. Code, Tehran, 14399-55991, Iran.
| | - Sasan Arian-Kia
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, North Kargar St, P.O.BOX:14395-433, Po. Code, Tehran, 14399-55991, Iran
| | - Soheila Manifar
- Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Fatahzadeh
- Division of Oral Medicine, Department of Oral Medicine, Rutgers School of Dental Medicine, 110 Bergen Street, Newark, NJ, 07103, USA
| | - Sajad Kolahdooz
- Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran
| | - Mansour Davoudi
- Department of Computer Science and Engineering and IT, School of Electrical and Computer Engineering, Shiraz University, Shiraz, Iran
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Perez-Wert P, Fernandez-Hernandez S, Gamez-Pozo A, Arranz-Alvarez M, Ghanem I, López-Vacas R, Díaz-Almirón M, Méndez C, Fresno Vara JÁ, Feliu J, Trilla-Fuertes L, Custodio A. Layer Analysis Based on RNA-Seq Reveals Molecular Complexity of Gastric Cancer. Int J Mol Sci 2024; 25:11371. [PMID: 39518924 PMCID: PMC11545517 DOI: 10.3390/ijms252111371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/14/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Gastric adenocarcinoma (GA) is a significant global health issue with poor prognosis, despite advancements in treatment. Although molecular classifications, such as The Cancer Genome Atlas (TCGA), provide valuable insights, their clinical utility remains limited. We performed a multi-layered functional analysis using TCGA RNA sequencing data to better define molecular subtypes and explore therapeutic implications. We reanalyzed TCGA RNA-seq data from 142 GA patients with localized disease who received adjuvant chemotherapy. Our approach included probabilistic graphical models and recurrent sparse k-means/consensus cluster algorithms for layer-based analysis. Our findings revealed survival differences among TCGA groups, with the GS subtype showing the poorest prognosis. We identified twelve functional nodes and seven biological layers, each with distinct functions. The combined molecular layer (CML) classification identified three prognostic groups that align with TCGA subtypes. CML2 (GS-like) displayed gene expression related to lipid metabolism, correlating with worse survival. Transcriptomic heterogeneity within the CIN subtype revealed clusters tied to proteolysis and lipid metabolism. We identified a subset of CIN tumors with profiles similar to MSI, termed CIN-MSI-like. Claudin-18, a key gene in proteolysis, was overexpressed across TCGA subtypes, suggesting it is a potential therapeutic target. Our study advances GA biology, enabling refined stratification and personalized treatment. Further studies are needed to translate these findings into clinical practice.
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Affiliation(s)
- Pablo Perez-Wert
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
| | - Sara Fernandez-Hernandez
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Angelo Gamez-Pozo
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Marina Arranz-Alvarez
- IdiPAZ Biobank, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain;
| | - Ismael Ghanem
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
| | - Rocío López-Vacas
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Mariana Díaz-Almirón
- Biostatistics Unit, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain;
| | - Carmen Méndez
- Department of Pathology, Hospital Universitario La Paz, 28046 Madrid, Spain;
| | - Juan Ángel Fresno Vara
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Jaime Feliu
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Universidad Autónoma de Madrid, 28046 Madrid, Spain
- Medicine Department, Universidad Autónoma de Madrid, 28046 Madrid, Spain
| | - Lucia Trilla-Fuertes
- Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (S.F.-H.); (A.G.-P.); (R.L.-V.); (J.Á.F.V.)
| | - Ana Custodio
- Department of Medical Oncology, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain; (P.P.-W.); (I.G.); (J.F.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
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Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
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Najafi D, Siri G, Sadri M, Yazdani O, Esbati R, Karimi P, Keshavarz A, Mehmandar-Oskuie A, Ilktac M. Combination MEG3 lncRNA and Ciprofloxacin dramatically decreases cell migration and viability as well as induces apoptosis in GC cells in vitro. Biotechnol Appl Biochem 2024; 71:809-816. [PMID: 38499448 DOI: 10.1002/bab.2578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 02/25/2024] [Indexed: 03/20/2024]
Abstract
Gastric cancer (GC) is a prominent cause of cancer-related mortality worldwide. Long noncoding RNA (lncRNA) maternal expression gene3 (MEG3) participates in numerous signaling pathways by targeting the miRNA-mRNA axis. Studies on human tumors have demonstrated that the antibiotic Ciprofloxacin induces cell cycle changes, programmed cell death, and growth suppression. In this study, we transfected MEG3 lncRNA and Ciprofloxacin into the MKN-45 GC cell line. qRT-PCR was employed to evaluate the effects on the specific microRNA and mRNA. The wound healing test, MTT assay, and flow cytometry were used to assess the impact of their administration on cell migration, viability, and apoptosis, respectively. Research showed that miR-147 expression fell even more after MEG3 lncRNA transfection, leading to an increase in B-cell lymphoma 2 (BCL-2) levels. Ciprofloxacin transfection did not significantly affect the axis, except for MEG3, which led to its slight upregulation. MEG3 lncRNA inhibited the migration of MKN-45 cells compared to the control group. When MEG3 lncRNA was coupled with Ciprofloxacin, there was a significant reduction in cell migration compared to untreated groups and controls. MTT assay and flow cytometry demonstrated that MEG3 lncRNA decreased cell viability and triggered apoptosis. Simultaneous administration of MEG3 lncRNA and Ciprofloxacin revealed a significant reduction in cell viability caused by increased apoptosis obtained from MTT or flow cytometry assays. Modulating the miR-147-BCL-2 axis decreases cell migration and survival while promoting cell death. In conclusion, combining MEG3 lncRNA with Ciprofloxacin may be an effective therapeutic approach for GC treatment by influencing the miR-14-BCl-2 axis, resulting in reduced cell viability, migration, and increased apoptosis.
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Affiliation(s)
- Dena Najafi
- Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus, Turkey
| | - Goli Siri
- Department of Internal Medicine, Amir Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Sadri
- Department of Internal Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Omid Yazdani
- Department of Medical Science, School of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Romina Esbati
- Research Center for Social Determinants of Health, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvin Karimi
- Fars Population-Based Cancer Registry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirreza Mehmandar-Oskuie
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehmet Ilktac
- Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus, Turkey
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9
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Boicean A, Boeras I, Birsan S, Ichim C, Todor SB, Onisor DM, Brusnic O, Bacila C, Dura H, Roman-Filip C, Ognean ML, Tanasescu C, Hasegan A, Bratu D, Porr C, Roman-Filip I, Neamtu B, Fleaca SR. In Pursuit of Novel Markers: Unraveling the Potential of miR-106, CEA and CA 19-9 in Gastric Adenocarcinoma Diagnosis and Staging. Int J Mol Sci 2024; 25:7898. [PMID: 39063140 PMCID: PMC11277351 DOI: 10.3390/ijms25147898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Gastric cancer stands as the fourth leading cause of cancer-related deaths globally, primarily comprising adenocarcinomas, categorized by anatomic location and histologic type. Often diagnosed at advanced stages, gastric cancer prognosis remains poor. To address the critical need for accurate tumoral markers for gastric cancer diagnosis, we conducted a study to assess classical markers like CEA and CA-19-9 alongside the novel marker miR-106. Our investigation revealed distinct dynamics of these markers compared to non-cancerous groups, although no disparities were observed across different disease stages. Univariable and multivariable logistic regression analyses demonstrated that elevated levels of miR-106, CEA and CA 19-9 were predictive of a positive histopathological exam, with the respective odds ratios of 12.032 (95% CI: 1.948-74.305), 30 (95% CI: 3.141-286.576), and 55.866 (95% CI: 4.512-691.687). Subsequently, we utilized predicted probabilities from regression models to construct receiver operating characteristic (ROC) curves, identifying CA 19-9 as the optimal predictor for gastric adenocarcinoma diagnosis when considering age and gender, with an area under the curve (AUC) of 0.936 (p < 0.001). Hence, classical markers exhibit superior performance compared to the novel marker miR-106 in predicting gastric adenocarcinoma.
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Affiliation(s)
- Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Ioana Boeras
- Molecular Biology Laboratory of the Applied Ecology Research Center, Faculty of Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
- Faculty of Social Sciences, Lucian Blaga University of Sibiu, 550012 Sibiu, Romania
| | - Sabrina Birsan
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Cristian Ichim
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Samuel Bogdan Todor
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Danusia Maria Onisor
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania; (D.M.O.); (O.B.)
| | - Olga Brusnic
- Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Târgu Mures, Romania; (D.M.O.); (O.B.)
| | - Ciprian Bacila
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Horatiu Dura
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Corina Roman-Filip
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Maria Livia Ognean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Ciprian Tanasescu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Adrian Hasegan
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Dan Bratu
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
| | - Corina Porr
- County Clinical Emergency Hospital of Sibiu, 550245 Sibiu, Romania
| | - Iulian Roman-Filip
- Department of Neurology, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology, 540136 Targu Mures, Romania
| | - Bogdan Neamtu
- Pediatric Research Department, Pediatric Clinical Hospital Sibiu, 550166 Sibiu, Romania;
| | - Sorin Radu Fleaca
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania; (A.B.); (C.I.); (C.B.); (H.D.); (C.R.-F.); (M.L.O.); (C.T.); (A.H.); (D.B.); (S.R.F.)
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10
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Shaker F, Razi S, Rezaei N. Circulating miRNA and circulating tumor DNA application as liquid biopsy markers in gastric cancer. Clin Biochem 2024; 129:110767. [PMID: 38705444 DOI: 10.1016/j.clinbiochem.2024.110767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
Liquid biopsy has been investigated as a novel method to overcome the numerous challenges in gastric cancer (GC) management. This non-invasive, feasible, and easy-to-repeat method has been shown to be cost-effective and capable of increasing diagnostic sensitivity and prognostic assessment. Additionally, it is potentially accurate to aid decision-making and personalized treatment planning. MicroRNA (miRNA) and circulating tumor DNA (ctDNA) markers can enhance GC management in various aspects, including diagnosis (mainly earlier diagnosis and the ability to perform population-based screening), prognosis (more precise stratification of prognosis), and treatment (including more accurate prediction of treatment response and earlier detection of resistance to the treatment). Concerning the treatment-related application, miRNAs' mimics and antagonists (by using two main strategies of restoring tumor suppressor miRNAs and inhibiting oncogene miRNAs) have been shown to be effective therapeutic agents. However, these need to be further validated in clinical trials. Furthermore, novel delivery systems, such as lipid-based vectors, polymeric-based vectors, and exosome-based delivery, have been developed to enhance the performance of these agents. Moreover, this paper explores the current detection and measuring methods for these markers. These approaches are categorized into direct methods (e.g., Chem-NAT, HTG EdgeSeq, and Multiplex Circulating Fireplex) and indirect methods (e.g., Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), qPCR, microarray, and NGS) for miRNA detection. For ctDNA measurement, main core technologies like NGS, digital PCR, real-time PCR, and mass spectrometry are suggested.
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Affiliation(s)
- Farhad Shaker
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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11
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Romańczyk M, Osmola M, Link A, Druet A, Hémont C, Martin J, Chapelle N, Matysiak-Budnik T. Non-Invasive Markers for the Detection of Gastric Precancerous Conditions. Cancers (Basel) 2024; 16:2254. [PMID: 38927959 PMCID: PMC11202181 DOI: 10.3390/cancers16122254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Gastric cancer (GC) is still one of the most prevalent cancers worldwide, with a high mortality rate, despite improvements in diagnostic and therapeutic strategies. To diminish the GC burden, a modification of the current diagnostic paradigm, and especially endoscopic diagnosis of symptomatic individuals, is necessary. In this review article, we present a broad review and the current knowledge status on serum biomarkers, including pepsinogens, gastrin, Gastropanel®, autoantibodies, and novel biomarkers, allowing us to estimate the risk of gastric precancerous conditions (GPC)-atrophic gastritis and gastric intestinal metaplasia. The aim of the article is to emphasize the role of non-invasive testing in GC prevention. This comprehensive review describes the pathophysiological background of investigated biomarkers, their status and performance based on available data, as well as their clinical applicability. We point out future perspectives of non-invasive testing and possible new biomarkers opportunities.
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Affiliation(s)
- Marcin Romańczyk
- Department of Gastroenterology, Academy of Silesia, 40-555 Katowice, Poland
- H-T. Medical Center, 43-100 Tychy, Poland
| | | | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Amaury Druet
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
| | - Caroline Hémont
- CHU de Nantes, Laboratoire d’Immunologie, Center for ImmunoMonitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
| | - Jerome Martin
- CHU de Nantes, Laboratoire d’Immunologie, Center for ImmunoMonitoring Nantes-Atlantique (CIMNA), F-44000 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Nicolas Chapelle
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Tamara Matysiak-Budnik
- IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, F-44093 Nantes, France
- University of Nantes, INSERM, Centre de Recherche Translationnel en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
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12
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Wu P, Zhang Y, Lyu Y, Chen J, Jiang Y, Xiang J, Liu B, Wu C. MiRNA polymorphisms affect the prognosis of gastric cancer: insights from Xianyou, Fujian. Front Oncol 2024; 14:1355270. [PMID: 38817897 PMCID: PMC11138161 DOI: 10.3389/fonc.2024.1355270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 04/22/2024] [Indexed: 06/01/2024] Open
Abstract
Introduction Gastric cancer, characterized by high incidence and substantial disease burden, has drawn continuous attention regarding its occurrence and prognosis. Genetics plays a crucial role in influencing the prognosis of gastric cancer, and single nucleotide polymorphisms are closely associated with the occurrence, development, and prognosis of this malignant tumor. Our study aims to conduct survival analysis on patients carrying different single nucleotide polymorphisms, exploring the relationship between miRNA single nucleotide polymorphisms and the prognosis of gastric cancer. Methods Genetic data from 344 patients in Xianyou, Fujian, formed the basis of our study. We delineated the survival rate and median survival time, utilizing the log-rank test and COX regression analysis as statistical tools. Results Upon stratifying the data by sex or operation, it was discerned that the GG genotype at MSH2 rs17502941 independently posed a heightened risk for gastric cancer. Other stratification analyses suggested that the subsequent single nucleotide polymorphisms were correlated with patient prognosis: rs17502941, rs884225, rs1468063, rs7143252, and rs2271738. Discussion The outcomes of this study strongly suggest that miRNA polymorphisms significantly influence the survival time of gastric cancer patients and can serve as effective predictors for the prognosis of gastric cancer.
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Affiliation(s)
- Ping Wu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yuling Zhang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yanping Lyu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Jingwen Chen
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Yu Jiang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Jianjun Xiang
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Baoying Liu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Chuancheng Wu
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, China
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13
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Lederer T, Hipler NM, Thon C, Kupcinskas J, Link A. Comparison of Fecal MicroRNA Isolation Using Various Total RNA Isolation Kits. Genes (Basel) 2024; 15:498. [PMID: 38674432 PMCID: PMC11050405 DOI: 10.3390/genes15040498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/09/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
Fecal specimens have long been regarded as promising sources for gastrointestinal cancer screening and have, thus, been extensively investigated in biomarker research. MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in regulating various biological processes. They are commonly dysregulated during tumor development and exhibit differential expression in feces. To assess the preanalytical feasibility of fecal miRNA analysis, we systematically compared the performance of commonly used total RNA extraction methods. Fecal samples from healthy subjects were utilized for this evaluation. Various methods, including miRNeasy, Universal, Trizol, RNeasy, and mirVana kits, were employed to isolate total RNA. MiRNA expression analyses were conducted using TaqMan or SYBR Green qRT-PCR for a subset of miRNAs, with externally spiked-in cel-miR-39 used for normalization. Most methods demonstrated similar performance in terms of the total RNA concentration and purity. Externally spiked cel-miR-39 and endogenous miRNAs (RNU6b, miR-16, and miR-21) exhibited comparable concentrations across the different RNA isolation methods, whereas the RNeasy mini kit consistently yielded lower values. Our findings suggest that various isolation methods produce reproducible and comparable miRNA expression results, supporting the potential comparability and translational applicability of miRNA-based biomarker research in the future.
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Affiliation(s)
- Theresa Lederer
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Noam M. Hipler
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39120 Magdeburg, Germany
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14
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Zhang Q, Du Z, Wang X, Li F, Liu Y, Sun J, Zhang L, Xiao Y, Lu X, Yu H, Liu T. Cell-free Nucleic Acid as Promising Diagnostic Biomarkers for Gastric Cancer: a Systematic Review. J Cancer 2024; 15:2900-2912. [PMID: 38706900 PMCID: PMC11064260 DOI: 10.7150/jca.92704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/09/2024] [Indexed: 05/07/2024] Open
Abstract
Background: Gastric cancer (GC) is a common malignancy with early detection being crucial for survival. Liquid biopsy analysis using cell-free nucleic acid is a preferred method for detection. Hence, we conducted a systematic review to assess the diagnostic efficacy of cell-free nucleic acid markers for GC. Methods: We searched PubMed and ISI Web of Science databases for articles that conformed to our inclusion and exclusion criteria from 2012 to 2022. The following information was abstracted: first author, year of publication, country/region, age, male proportion, tumor stage for cases, specimen type, measurement method, targeted markers and diagnostic related indicators (including sensitivity, specificity, AUC, P-value). Results: Fifty-eight studies examined cell-free RNAs (cfRNAs) with a total of 62 individual circulating markers and 7 panels in serum or plasma, while 21 studies evaluated cell-free DNAs (cfDNAs) with 29 individual circulating markers and 7 panels. For individual cfRNAs, the median (range) sensitivity and specificity were 80% (21% - 98%) and 80% (54% - 99%), respectively. The median (range) sensitivity and specificity for cfRNA panels were 86% (83% - 90%) and 75% (60% - 98%), respectively. In comparison, the median (range) sensitivity and specificity reported for individual cfDNAs were 50% (18% - 96%) and 93% (57% - 100%), respectively, while cfDNA panels had a median (range) sensitivity and specificity of 85% (41% - 92%) and 73.5% (38% - 90%), respectively. The meta results indicate that cfRNA markers exhibit high sensitivity (80%) and low specificity (80%) for detecting GC, while cfDNA markers have lower sensitivity (59%) but higher specificity (92%). Conclusions: This review has demonstrated that cell-free nucleic acids have the potential to serve as useful diagnostic markers for GC. Given that both cfRNA and cfDNA markers have shown promising diagnostic performance for GC, the combination of the two may potentially enhance diagnostic efficiency.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Haixin Yu
- Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tao Liu
- Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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15
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Lukosevicius R, Alzbutas G, Varkalaite G, Salteniene V, Tilinde D, Juzenas S, Kulokiene U, Janciauskas D, Poskiene L, Adamonis K, Kiudelis G, Kupcinskas J, Skieceviciene J. 5'-Isoforms of miR-1246 Have Distinct Targets and Stronger Functional Impact Compared with Canonical miR-1246 in Colorectal Cancer Cells In Vitro. Int J Mol Sci 2024; 25:2808. [PMID: 38474054 DOI: 10.3390/ijms25052808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/05/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is a multifactorial disease involving genetic and epigenetic factors, such as miRNAs. Sequencing-based studies have revealed that miRNAs have many isoforms (isomiRs) with modifications at the 3'- and 5'-ends or in the middle, resulting in distinct targetomes and, consequently, functions. In the present study, we aimed to evaluate the putative targets and functional role of miR-1246 and its two 5'-isoforms (ISO-miR-1246_a and ISO-miR-1246_G) in vitro. Commercial Caco-2 cells of CRC origin were analyzed for the expression of WT-miR-1246 and its 5'-isoforms using small RNA sequencing data, and the overabundance of the two miR-1246 isoforms was determined in cells. The transcriptome analysis of Caco-2 cells transfected with WT-miR-1246, ISO-miR-1246_G, and ISO-miR-1246_a indicated the minor overlap of the targetomes between the studied miRNA isoforms. Consequently, an enrichment analysis showed the involvement of the potential targets of the miR-1246 isoforms in distinct signaling pathways. Cancer-related pathways were predominantly more enriched in dysregulated genes in ISO-miR-1246_G and ISO-miR-1246_a, whereas cell cycle pathways were more enriched in WT-miR-1246. The functional analysis of WT-miR-1246 and its two 5'-isoforms revealed that the inhibition of any of these molecules had a tumor-suppressive role (reduced cell viability and migration and promotion of early cell apoptosis) in CRC cells. However, the 5'-isoforms had a stronger effect on viability compared with WT-miR-1246. To conclude, this research shows that WT-miR-1246 and its two 5'-isoforms have different targetomes and are involved in distinct signaling pathways but collectively play an important role in CRC pathogenesis.
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Affiliation(s)
- Rokas Lukosevicius
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Gediminas Alzbutas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Greta Varkalaite
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Violeta Salteniene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Deimante Tilinde
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Simonas Juzenas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Institute of Biotechnology, Life Science Centre, Vilnius University, LT-10257 Vilnius, Lithuania
| | - Ugne Kulokiene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Dainius Janciauskas
- Department of Pathology, Medical Academy, Hospital of Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Lina Poskiene
- Department of Pathology, Medical Academy, Hospital of Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Kestutis Adamonis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Gediminas Kiudelis
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
- Department of Gastroenterology, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Academy of Medicine, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania
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16
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Pengjie Y, Rong J, Pengfei N. miR-378a-5p exerts tumor-suppressive effects on esophageal squamous cell carcinoma after neoadjuvant immunotherapy by downregulating APOC1/CEP55. Sci Rep 2024; 14:305. [PMID: 38172247 PMCID: PMC10764758 DOI: 10.1038/s41598-023-50938-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 12/28/2023] [Indexed: 01/05/2024] Open
Abstract
Genetic assessment of tumors following neoadjuvant immunotherapy helps identifying targets that mediate anti-tumor immunity. In this study, we explored dysregulated RNAs in esophageal squamous cell carcinoma samples after neoadjuvant immunotherapy using deep sequencing and high-throughput screening. We identified 584 differentially expressed messenger RNAs (mRNAs), 67 differentially expressed microRNAs (miRNAs), and 1,047 differentially expressed long non-coding RNAs (lncRNAs) using differential expression analysis. Competing endogenous RNAs closely related to esophageal squamous cell carcinoma were selected via a combined Pearson's correlation test and weighted correlation network analysis. After validation using survival analysis and dry-lab and wet-lab-based studies, we identified the I-miR-378-5p-APOC1/CEP55 as a critical pathway for esophageal squamous cell carcinoma progression after neoadjuvant immunotherapy. Tumor immune infiltration analysis showed that APOC1 and CEP55 expression is associated with immune regulatory pathways and the function of multiple infiltrating immune cells. We investigated the mechanism of esophageal squamous carcinoma progression after neoadjuvant immunotherapy from the perspective of the mRNA-miRNA-lncRNA network. Furthermore, we identified accurate novel therapeutic targets and prognostic biomarkers, introduced novel perspectives to immunotherapy studies, and laid the foundation for the clinical treatment of patients with esophageal squamous carcinoma.
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Affiliation(s)
- Yang Pengjie
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China
- Thoracic Surgery Department, Peking University Cancer Hospital Inner Mongolia Hospital (Cancer Hospital Affiliated to Inner Mongolia Medical University), Hohhot, 010110, Inner Mongolia Autonomous Region, China
| | - Jia Rong
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China
| | - Ning Pengfei
- Inner Mongolia Medical University, Jinshan Development Zone, Hohhot, 010110, Inner Mongolia Autonomous Region, China.
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17
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Tjandra D, Busuttil RA, Boussioutas A. Gastric Intestinal Metaplasia: Challenges and the Opportunity for Precision Prevention. Cancers (Basel) 2023; 15:3913. [PMID: 37568729 PMCID: PMC10417197 DOI: 10.3390/cancers15153913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/20/2023] [Accepted: 07/27/2023] [Indexed: 08/13/2023] Open
Abstract
GIM is a persistent, premalignant lesion whereby gastric mucosa is replaced by metaplastic mucosa resembling intestinal tissue, arising in the setting of chronic inflammation, particularly in the context of Helicobacter pylori. While the overall rates of progression to gastric adenocarcinoma are low, estimated at from 0.25 to 2.5%, there are features that confer a much higher risk and warrant follow-up. In this review, we collate and summarise the current knowledge regarding the pathogenesis of GIM, and the clinical, endoscopic and histologic risk factors for cancer. We examine the current state-of-practice with regard to the diagnosis and management of GIM, which varies widely in the published guidelines and in practice. We consider the emerging evidence in population studies, artificial intelligence and molecular markers, which will guide future models of care. The ultimate goal is to increase the detection of early gastric dysplasia/neoplasia that can be cured while avoiding unnecessary surveillance in very low-risk individuals.
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Affiliation(s)
- Douglas Tjandra
- Central Clinical School, Monash University, 99 Commercial Rd, Melbourne, VIC 3004, Australia;
- Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004, Australia
| | - Rita A. Busuttil
- Central Clinical School, Monash University, 99 Commercial Rd, Melbourne, VIC 3004, Australia;
- Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004, Australia
| | - Alex Boussioutas
- Central Clinical School, Monash University, 99 Commercial Rd, Melbourne, VIC 3004, Australia;
- Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004, Australia
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18
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Ju Y, Choi GE, Lee MW, Jeong M, Kwon H, Kim DH, Kim J, Jin H, Lee KE, Hyun KY, Jang A. Identification of miR-143-3p as a diagnostic biomarker in gastric cancer. BMC Med Genomics 2023; 16:135. [PMID: 37328880 PMCID: PMC10273760 DOI: 10.1186/s12920-023-01554-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/19/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is among the most common types of gastrointestinal cancers and has a high incidence and mortality around the world. To suppress the progression of GC, it is essential to develop diagnostic markers. MicroRNAs regulate GC development, but a clearer insight into their role is needed before they can be applied as a molecular markers and targets. METHODS In this study, we assessed the diagnostic value of differentially expressed microRNAs as potential diagnostic biomarkers for GC using data for 389 tissue samples from the Cancer Genome Atlas (TCGA) and 21 plasma samples from GC patients. RESULTS The expression of hsa-miR-143-3p (also known as hsa-miR-143) was significantly downregulated in GC according to the TCGA data and plasma samples. The 228 potential target genes of hsa-miR-143-3p were analyzed using a bioinformatics tool for miRNA target prediction. The target genes correlated with extracellular matrix organization, the cytoplasm, and identical protein binding. Furthermore, the pathway enrichment analysis of target genes showed that they were involved in pathways in cancer, the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, and proteoglycans in cancer. The hub genes in the protein-protein interaction (PPI) network, were matrix metallopeptidase 2 (MMP2), CD44 molecule (CD44), and SMAD family member 3 (SMAD3). CONCLUSIONS This study suggests that hsa-miR-143-3p may be used as a diagnostic marker for GC, contributing via the pathways involved in the development of GC.
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Affiliation(s)
- Yeongdon Ju
- Medical Science Research Center, Pusan National University, Yangsan, 50612, Republic of Korea
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Go-Eun Choi
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Moon Won Lee
- Division of Gastroenterology, Pusan National University Hospital, Busan, 49241, Republic of Korea
- Department of Internal Medicine, Pusan National University College of Medicine, Busan, 49241, Republic of Korea
| | - Myeongguk Jeong
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Hyeokjin Kwon
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Dong Hyeok Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Jungho Kim
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Hyunwoo Jin
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Kyung Eun Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, 46252, Republic of Korea
| | - Kyung-Yae Hyun
- Department of Clinical Laboratory Science, Dong-Eui University, Busan, 47340, Republic of Korea.
| | - Aelee Jang
- Department of Nursing, University of Ulsan, Ulsan, 44610, Republic of Korea.
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Saller J, White D, Hough B, Yoder S, Whiting J, Chen DT, Magliocco A, Coppola D. An miRNA Signature Predicts Grading of Pancreatic Neuroendocrine Neoplasms. Cancer Genomics Proteomics 2023; 20:154-164. [PMID: 36870693 PMCID: PMC9989673 DOI: 10.21873/cgp.20370] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND/AIM Grading pancreatic neuroendocrine neoplasms (PNENs) via mitotic rate and Ki-67 index score is complicated by interobserver variability. Differentially expressed miRNAs (DEMs) are useful for predicting tumour progression and may be useful for grading. PATIENTS AND METHODS Twelve PNENs were selected. Four patients had grade (G) 1 pancreatic neuroendocrine tumours (PNETs); 4 had G2 PNETs; and 4 had G3 PNENs (2 PNETs and 2 pancreatic neuroendocrine carcinomas). Samples were profiled using the miRNA NanoString Assay. RESULTS There were 6 statistically significant DEMs between different grades of PNENs. MiR1285-5p was the sole miRNA differentially expressed (p=0.03) between G1 and G2 PNETs. Six statistically significant DEMs (miR135a-5p, miR200a-3p, miR3151-5p, miR-345-5p, miR548d-5p and miR9-5p) (p<0.05) were identified between G1 PNETs and G3 PNENs. Finally, 5 DEMs (miR155-5p, miR15b-5p, miR222-3p, miR548d-5p and miR9-5p) (p<0.05) were identified between G2 PNETs and G3 PNENs. CONCLUSION The identified miRNA candidates are concordant with their patterns of dysregulation in other tumour types. The reliability of these DEMs as discriminators of PNEN grades support further investigations using larger patient populations.
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Affiliation(s)
- James Saller
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Daley White
- Department of Biomedical Library, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Brooke Hough
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Sean Yoder
- Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Junmin Whiting
- Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Dung-Tsa Chen
- Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | | | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.; .,Department of Pathology Florida Digestive Health Specialists, Lakewood Ranch, FL, U.S.A
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20
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Guo Y, Cui X, Zhang Y, Ma X, Ren A, Huang H. Diagnostic and Prognostic Value of Serum miR-296-5p and miR-28-3p in Human Gastric Cancer. Cancer Biother Radiopharm 2023; 38:95-101. [PMID: 32898433 DOI: 10.1089/cbr.2020.4144] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background: Previous studies reported the use of microRNAs (miRNAs) as diagnostic and/or prognostic biomarkers for various cancers, including gastric cancer (GC). This study evaluated the diagnostic and prognostic significance of serum miR-296-5p and miR-28-3p in GC. Materials and Methods: Serum samples of 90 patients with GC and 90 healthy individuals, and 20 pairs of tissue specimens from patients with GC were collected. The expression of miR-296-5p and miR-28-3p in both the serum and tissue samples were detected using quantitative real-time polymerase chain reaction analysis. The diagnostic and prognostic values of miR-296-5p and miR-28-3p were evaluated by using receiver operating characteristic curve and Kaplan-Meier analyses, respectively. Results: Compared with the healthy controls, the expression of miR-296-5p in the serum and tissues of patients with GC was significantly upregulated, whereas that of miR-28-3p was significantly downregulated. High miR-296-5p and low miR-28-3p levels in the serum significantly correlated with larger tumor size (>5 cm), lymph node metastasis, and TNM stage III+IV. The area under the curve values of miR-296-5p and miR-28-3p were 0.919 and 0.911, respectively, with high sensitivity and specificity. Kaplan-Meier survival curves showed that patients with GC with high level of miR-296-5p or low level of miR-1236-3p in the serum had the poorest overall survival. COX analysis showed that lymphatic metastasis, high miR-296-5p expression, and low miR-28-3p expression are independent parameters indicating poor prognosis in GC. Conclusion: Our findings indicate that serum miR-296-5p and miR-28-3p levels are potential biomarkers in the diagnosis and prognosis of GC.
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Affiliation(s)
- Yuntong Guo
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
| | - Xiaolong Cui
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
| | - Yu Zhang
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
| | - Xiaobo Ma
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
| | - Aigang Ren
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
| | - He Huang
- Department of Gastrointestinal Surgery, First Hospital of ShanXi Medical University, Taiyuan City, China
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Gu XJ, Li YJ, Wang F, Ye T. MiR-30e-3p inhibits gastric cancer development by negatively regulating THO complex 2 and PI3K/AKT/mTOR signaling. World J Gastrointest Oncol 2022; 14:2170-2182. [PMID: 36438699 PMCID: PMC9694264 DOI: 10.4251/wjgo.v14.i11.2170] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/05/2022] [Accepted: 10/12/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common type of digestive cancer with high morbidity and mortality rates worldwide. Considerable effort has been expended in understanding the mechanism of GC development and metastasis. The current study therefore explores the involvement of microRNAs in the regulation of GC progression.
AIM To explore the expression and function of miR-30e-3p in GC development.
METHODS MiR-30e-3p was found to be downregulated in GC, with low levels thereof predicting poor outcomes among patients with GC. Functionally, we revealed that miR-30e-3p suppressed cell growth and metastatic behaviors of GC cells. Bioinformatics analysis predicted that THO complex 2 (THOC2) was a direct target of miR-30e-3p, and the interaction between miR-30e-3p and THOC2 was further validated by a luciferase reporter assay.
RESULTS Our findings revealed that knockdown of THOC2 inhibited the growth and metastatic behaviors of GC cells. After investigating signaling pathways involved in miR-30e-3p regulation, we found that the miR-30e-3p/THOC2 axis regulated the PI3K/AKT/mTOR pathway in GC.
CONCLUSION Our findings suggest the novel functional axis miR-30e-3p/THOC2 is involved in GC development and progression. The miR-30e-3p/THOC2 axis could be utilized to develop new therapies against GC.
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Affiliation(s)
- Xiao-Jing Gu
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Prefecture, China
| | - Ya-Jun Li
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Prefecture, China
| | - Fang Wang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Prefecture, China
| | - Ting Ye
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Prefecture, China
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22
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Ma X, Ou K, Liu X, Yang L. Application progress of liquid biopsy in gastric cancer. Front Oncol 2022; 12:969866. [PMID: 36185234 PMCID: PMC9521037 DOI: 10.3389/fonc.2022.969866] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors globally. Guiding the individualized treatment of GC is the focus of research. Obtaining representative biological samples to study the biological characteristics of GC is the focus of diagnosis and treatment of GC. Liquid biopsy technology can use high-throughput sequencing technology to detect biological genetic information in blood. Compared with traditional tissue biopsy, liquid biopsy can determine the dynamic changes of tumor. As a noninvasive auxiliary diagnostic method, liquid biopsy can provide diagnostic and prognostic information concerning the progression of the disease. Liquid biopsy includes circulating tumor cells, circulating tumor DNA, circulating tumor RNA, tumor educated platelets, exosomes, and cytokines. This article describes the classification of liquid biopsy and its application value in the occurrence, development, and therapeutic efficacy of GC.
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Transcriptome Sequencing Analysis of the Effect of β-Elemene on Colorectal Cancer from the lncRNA-miRNA-mRNA Perspective. Genet Res (Camb) 2022; 2022:5896296. [PMID: 36160034 PMCID: PMC9489404 DOI: 10.1155/2022/5896296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022] Open
Abstract
Object. β-Elemene is an emerging antitumor Chinese medicine, but the exact mechanism of action of β-elemene in colorectal cancer (CRC) remains unclear. This study aimed to explore the mechanism of the lncRNA-miRNA-mRNA network in the process of β-elemene inhibiting CRC. Methods. RNA sequencing was performed on CRC cells from the control group (untreated) and the case group (β-elemene-treated). According to the sequencing data, we screened the differentially expressed (DE) lncRNAs, miRNAs, and mRNAs and then analyzed them by functional enrichment analyses. Through the lncRNA-miRNA-mRNA network, the key miRNAs and mRNAs involved in the process of β-elemene inhibiting CRC were further identified. Results. Totally, 607 upregulated and 599 downregulated DElncRNAs, 12 downregulated and 24 upregulated DEmiRNAs, and 3153 downregulated and 3248 upregulated DEmRNAs were identified. Through the lncRNA-miRNA-mRNA network, 3 miRNAs (miR-7109-3p, miR-4506, and miR-3182), 7 prognostic mRNAs (ALPG, DTX1, HOXD13, RIMS3, SLC16A8, SYT1, and TNNT1), and 2 key mRNAs (RIMS3 and SLC16A8) were determined to participate in the inhibitory mechanism of β-elemene in CRC. Conclusion. This study revealed for the first time that the lncRNA-miRNA-mRNA network is involved in the regulation of β-elemene in CRC, and these identified miRNAs and mRNAs could be new clinical prognostic biomarkers and therapeutic targets for CRC patients.
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24
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Shatila M, Thomas AS. Current and Future Perspectives in the Diagnosis and Management of Helicobacter pylori Infection. J Clin Med 2022; 11:jcm11175086. [PMID: 36079015 PMCID: PMC9456682 DOI: 10.3390/jcm11175086] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 12/03/2022] Open
Abstract
Helicobacter pylori (Hp) is a prevalent organism infecting almost half the global population. It is a significant concern, given its associated risk of gastric cancer, which is the third leading cause of cancer death globally. Infection can be asymptomatic or present with dyspeptic symptoms. It may also present with alarm symptoms in the case of progression to cancer. Diagnosis can be achieved non-invasively (breath tests, stool studies, or serology) or invasively (rapid urease test, biopsy, or culture). Treatment involves acid suppression and regimens containing several antibiotics and is guided by resistance rates. Eradication is essential, as it lowers the risk of complications and progression to cancer. Follow-up after eradication is similarly important, as the risk of cancer progression remains. There have been many recent advances in both diagnosis and treatment of Hp. In particular, biosensors may be effective diagnostic tools, and nanotechnology, vaccines, and potassium-competitive acid blockers may prove effective in enhancing eradication rates.
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25
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Zingone F, Pilotto V, Cardin R, Maddalo G, Orlando C, Fassan M, Marsilio I, Collesei E, Pelizzaro F, Farinati F. Autoimmune Atrophic Gastritis: The Role of miRNA in Relation to Helicobacter Pylori Infection. Front Immunol 2022; 13:930989. [PMID: 35941891 PMCID: PMC9356369 DOI: 10.3389/fimmu.2022.930989] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/23/2022] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION MicroRNAs (miRNAs) have been proposed as diagnostic markers, biomarkers of neoplastic progression, and possible therapeutic targets in several immune-mediated diseases. We aimed to analyze the expression profile of selected miRNAs (miR21, miR142, miR223, miR155) in patients with autoimmune atrophic gastritis (AAG), patients with non-autoimmune multifocal atrophic gastritis (MAG), and healthy control subjects (HC). MATERIALS AND METHODS A total of 103 patients with AAG were consecutively recruited for this study among those attending our gastroenterology outpatient clinic. Participating patients were divided into two groups: primary, not Helicobacter pylori (HP)-associated related AAG (n=57, P-AAG) and HP-associated AAG (n=46, HP-AAG); this subgroup included HP-positive patients, patients with previously reported HP infection, and patients harboring antral atrophy, considered as a stigma of HP infection. We also included 20 sex-age-matched MAG patients and 10 HC. Upper endoscopy with gastric biopsies were performed on each AAG and MAG patient. Circulating levels of miR21-5p, miR142-3p, miR223-3p, and miR155-5p were measured by RT-PCR in all groups. RESULTS MiR-21 was over-expressed in P-AAG (p=0.02), HP-AAG (p = 0.04), and MAG (p=0.03) compared with HC. By contrast, miR-142 was more expressed in HC than in HP-AAG (p=0.04) and MAG (p=0.03). MiR-155 showed no significant differences among the four subgroups, while, unexpectedly, miR-223 was overexpressed in HC compared to P-AAG (p=0.01), HP-AAG (p=0.003), and MAG (p<0.001), and was higher in P-AAG than in MAG (p=0.05). CONCLUSIONS MiR-21 was over-expressed in patients with gastric precancerous conditions irrespective of etiology, while in the same subgroups miR-142 and miR-223 were under-expressed compared to healthy controls. Controlling miRNAs up- or downregulation could lead to a breakthrough in treating chronic autoimmune diseases and potentially interfere with the progression to cancer.
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Affiliation(s)
- Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
| | - Valentina Pilotto
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
| | - Romilda Cardin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Gemma Maddalo
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
| | - Costanza Orlando
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology Unit, University of Padua, Padua, Italy
- Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy
| | - Ilaria Marsilio
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Eugenio Collesei
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Gastroenterology Unit, Azienda Ospedale Università -Padova, Padua, Italy
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Circulating miR-141 as a potential biomarker for diagnosis, prognosis and therapeutic targets in gallbladder cancer. Sci Rep 2022; 12:10072. [PMID: 35710767 PMCID: PMC9203542 DOI: 10.1038/s41598-022-13430-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023] Open
Abstract
MicroRNA-141(miR-141) has been reported to play vital roles in the regulation of carcinogenesis and cancer progression. However, the biological function of miR-141 in GBC has received less attention. The aim of this study was to estimate the potential value of the expression level of miR-141 as a diagnostic and prognostic blood-based biomarker in gallbladder cancer (GBC) patients. Meanwhile, to explore its biological role in GBC cells. RT-PCR was employed to confirm the expression of miR-141 in ten paired tissue samples (10 GBC tissues and 10 adjacent normal gallbladder tissues), GBC cell lines and peripheral blood specimens from 98 GBC patients and 60 healthy controls. MTT assay was used to evaluate the GBC cells proliferation and flow cytometry was used to detect the cell apoptosis. Receiver operating characteristic curve analysis and the area under the curve (AUC) were used to evaluate the value of miR-141 plasma levels for GBC diagnosis. Finally, clinicopathological and survival data of all GBC patients were collected and analyzed. Here, we confirmed that the expression of miR-141 were upregulated in primary gallbladder cancer cells and tissues compared with human gallbladder epithelial cells and adjacent normal tissues (P < 0.0001). Meanwhile, we found that downregulated expression of miR-141 by miR-141 inhibitor could induce apoptosis and inhibit proliferation of GBC cells. Additionally, elevated plasma miR-141 expression was also detected in the peripheral blood of GBC patients compared with healthy controls (P < 0.0001). The AUC value of miR-141 for GBC diagnosis was 0.894 (95% CI 0.843–0.945), which was more valuable than those including carcinoembryonic antigen (CEA) (0.713, 95% CI 0.633–0.793), carbohydrate antigen 125 (CA125) (0.837, 95% CI 0.776–0.899) and carbohydrate antigen 19–9 (CA19-9) (0.869, 95% CI 0.813–0.924). The high expression level of miR-141 in plasma was significantly associated with tumor invasion (P = 0.008), lymph node metastasis (P < 0.0001) and advanced pathologic tumor/node/metastasis (pTNM) stage (P = 0.009). More importantly, high plasma miR-141 expression was an independent prognostic factor for predicting poorer long-term survival in GBC patients. Elevated expression of circulating miR-141 in peripheral blood might be a potential novel biomarker for diagnosis and prognosis of GBC patients. Downregulated expression of miR-141 could inhibit proliferation and induce apoptosis of GBC cells, that provide a potential therapeutic target for GBC.
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Petkevicius V, Thon C, Steponaitiene R, Skieceviciene J, Janciauskas D, Jechorek D, Malfertheiner P, Kupcinskas J, Link A. Differential Expression of Long Noncoding RNA HOTAIR in Intestinal Metaplasia and Gastric Cancer. Clin Transl Gastroenterol 2022; 13:e00483. [PMID: 35347094 PMCID: PMC9132515 DOI: 10.14309/ctg.0000000000000483] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 03/15/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION High expression of HOTAIR promotes tumor growth and carries a dismal prognosis for the patient. We investigated the prognostic value of HOTAIR expression in gastric cancer (GC) and systematically delineate the expression in relation to Helicobacter pylori infection and preneoplastic changes. METHODS HOTAIR expression was analyzed in surgical paired tissue samples of patients with GC and biopsy samples from patients with atrophic gastritis and/or intestinal metaplasia (AG ± -IM), chronic nonatrophic gastritis, and controls. The cancer genome atlas (TCGA) data were used for validation. HOTAIR expression was evaluated in sera and ascites of patients with GC. Quantitative HOTAIR expression analysis was performed using quantitative polymerase chain reaction, and LINE-1 methylation was assessed by bisulfite pyrosequencing. RESULTS HOTAIR was more frequently detected in tumor tissues compared with adjacent gastric mucosa (65.4% vs 8.6%). HOTAIR expression was associated with depth of tumor invasion and tumor location and with shorter overall survival in patients with diffuse-type GC as confirmed in the TCGA cohort. HOTAIR was not detectable in controls but was found in 2.2% of patients with chronic nonatrophic gastritis and 18.3% of patients with AG ± IM, which was further associated with IM, grade of IM, and H. pylori positivity. DISCUSSION HOTAIR expression was associated with GC and preneoplastic changes of stomach mucosa. Although HOTAIR expression was strongly linked to IM, HOTAIR expression was only associated with worse prognosis in Lauren diffuse and not intestinal type of GC. Further studies are needed to evaluate the value of HOTAIR as diagnostic and predictive biomarker in IM and translational therapeutic relevance of HOTAIR in diffuse-type GC.
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Affiliation(s)
- Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Ruta Steponaitiene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Dainius Janciauskas
- Department of Pathological Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania; and
| | - Doerthe Jechorek
- Institute of Pathology, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
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Furuke H, Konishi H, Arita T, Kataoka S, Shibamoto J, Takabatake K, Takaki W, Shimizu H, Yamamoto Y, Morimura R, Komatsu S, Shiozaki A, Ikoma H, Otsuji E. miR‑4730 suppresses the progression of liver cancer by targeting the high mobility group A1 pathway. Int J Mol Med 2022; 49:83. [PMID: 35485281 PMCID: PMC9106373 DOI: 10.3892/ijmm.2022.5139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/13/2022] [Indexed: 12/24/2022] Open
Abstract
As liver cancer (LC) is the sixth most commonly diagnosed malignancy, it is necessary to elucidate the molecular mechanisms responsible for LC progression. MicroRNAs (miRNAs/miRs) play crucial roles in tumor progression by regulating target gene expression. The present study assessed miRNA-4730 expression and function in LC. The effects of miR-4730 overexpression were examined in LC cell lines, and the target genes of miR-4730 were evaluated using microarray analysis and TargetScan data. In addition, the association between miR-4730 expression in tissue samples and the prognosis of 70 patients with LC was evaluated. miR-4730 expression was suppressed in LC tissues and cell lines. miR-4730 overexpression suppressed cell proliferation and cell cycle progression and promoted apoptosis. High mobility group A1 (HMGA1) was revealed as the direct target of miR-4730 using luciferase reporter assay, and the inhibition of downstream integrin-linked kinase (ILK) expression and Akt or glycogen synthase kinase 3β (GSK3β) phosphorylation was confirmed. The lower expression of miR-4730 in tissue samples was significantly associated with a worse recurrence-free survival of patients with LC. On the whole, miR-4730 suppressed tumor progression by directly targeting HMGA1 and inhibiting the ILK/Akt/GSK3β pathway. miR-4730 thus has potential for use as a prognostic marker and may prove to be a therapeutic target for miRNA-based therapies.
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Affiliation(s)
- Hirotaka Furuke
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Satoshi Kataoka
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Jun Shibamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Kazuya Takabatake
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Wataru Takaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Yusuke Yamamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602‑8566, Japan
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Chen S, Jundi D, Wang W, Ren C. LINC01857 promotes the proliferation, migration, and invasion of gastric cancer cells via regulating miR-4731-5p/HOXC6. Can J Physiol Pharmacol 2022; 100:689-701. [PMID: 35468304 DOI: 10.1139/cjpp-2021-0411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The great importance of long non-coding RNAs (lncRNAs) in tumorigenesis has been acknowledged gradually. LINC01857 is previously reported to be highly expressed in gastric cancer (GC), while the regulatory mechanism of LINC01857 in gastric cancer is largely unknown. In this study, we detected high expression of LINC01857 from the gastric cancer microarray GSE109476. Additionally, LINC01857 expression is remarkably up-regulated in gastric cancer cell lines (AGS, MKN-45, HGC-27 and SGC-7901) compared to the normal gastric mucosal cell line GES-1. Functionally, LINC01857 knockdown suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) of GC cells, while LINC01857 overexpression promoted the proliferation, migration, invasion and EMT of GC cells. Furthermore, our data demonstrate that LINC01857 targeted miR-4731-5p and subsequently increased the expression of HOXC6 in GC. Rescue experiments showed that miR-4731-5p inhibition and HOXC6 overexpression could reverse the biological behavior of GC cells induced by LINC01857 knockdown. In conclusion, we demonstrated that LINC01857 sponged miR-4731-5p to promote the expression of HOXC6 and eventually acts as an oncogene in GC.
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Affiliation(s)
| | - Dai Jundi
- Shandong Province, Department of Gastrointestinal Surgery, Yantai, China;
| | - Wei Wang
- Shandong Province, Department of Gastrointestinal Surgery, Yantai, China;
| | - Chenglei Ren
- Shandong Province, Department of Gastrointestinal Surgery, Yantai, China, 264000;
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30
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Li J, Xie B, Wang H, Chen C, Pan C, Jia J. Research on Function of Exosome of miR-328-3p Secreted by Bone Marrow Mesenchymal Stem Cells (BMSCs) on Restraining the Gastric Cancer Through Being Down-Regulated with Trefoil Factor 3. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Certain progress has been made in the therapeutic method against gastric cancer such as surgical operation combined with chemotherapy and radiation therapy in recent years. But the therapeutic efficacy and prognosis on gastric cancer was still not satisfactory. The function of exosome
of miR-328–3p secreted by bone marrow stromal cells (BMSCs) on restraining the gastric cancer was studied in the present study. The BMSCs with highly-expressed miR-328-3p was established. The exosome in cell supernatant was collected. The exosome of BMSCs and MSCs with highlyexpressed
miR-328-3p was added into SGC-7901 cells followed by analysis of miR-328-3p level by Real-time PCR and TFF3 (Trefoil Factor 3) level in exosome by Western blot, cell proliferation, expression of E-cadherin, Vimentin and Caspase-3. miR-328-39 expression was reduced and TFF3 was elevated in
gastric cancer tissue (P < 0.05). miR-328-3p was upregulated and TFF3 was downregulated after addition of BMSCs exosomes along with increased cell proliferation and reduced E-cadherin and Caspase3 expression (P < 0.05). In conclusion, exosome of BMSCs could be regulated
by miR-328-3p and TFF3 expression is restrained so as to regulate the biological behaviors of gastric cancer cell.
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Affiliation(s)
- Jing Li
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
| | - Bo Xie
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
| | - Hu Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
| | - Chengsong Chen
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
| | - Chengwu Pan
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
| | - Jianguang Jia
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China
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31
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Yang Q, Chen Y, Guo R, Dai Y, Tang L, Zhao Y, Wu X, Li M, Du F, Shen J, Yi T, Xiao Z, Wen Q. Interaction of ncRNA and Epigenetic Modifications in Gastric Cancer: Focus on Histone Modification. Front Oncol 2022; 11:822745. [PMID: 35155211 PMCID: PMC8826423 DOI: 10.3389/fonc.2021.822745] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 12/28/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer has developed as a very common gastrointestinal tumors, with recent effective advancements in the diagnosis and treatment of early gastric cancer. However, the prognosis for gastric cancer remains poor. As a result, there is in sore need of better understanding the mechanisms of gastric cancer development and progression to improve existing diagnostic and treatment options. In recent years, epigenetics has been recognized as an important contributor on tumor progression. Epigenetic changes in cancer include chromatin remodeling, DNA methylation and histone modifications. An increasing number of studies demonstrated that noncoding RNAs (ncRNAs) are associated with epigenetic changes in gastric cancer. Herein, we describe the molecular interactions of histone modifications and ncRNAs in epigenetics. We focus on ncRNA-mediated histone modifications of gene expression associated with tumorigenesis and progression in gastric cancer. This molecular mechanism will contribute to our deeper understanding of gastric carcinogenesis and progression, thus providing innovations in gastric cancer diagnosis and treatment strategies.
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Affiliation(s)
- Qingfan Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Yu Chen
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Rui Guo
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Yalan Dai
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Liyao Tang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Yueshui Zhao
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Xu Wu
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Mingxing Li
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Fukuan Du
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Jing Shen
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong SAR, China
| | - Zhangang Xiao
- South Sichuan Institute of Translational Medicine, Luzhou, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
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32
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Varkalaite G, Vaitkeviciute E, Inciuraite R, Salteniene V, Juzenas S, Petkevicius V, Gudaityte R, Mickevicius A, Link A, Kupcinskas L, Leja M, Kupcinskas J, Skieceviciene J. Atrophic gastritis and gastric cancer tissue miRNome analysis reveals hsa-miR-129-1 and hsa-miR-196a as potential early diagnostic biomarkers. World J Gastroenterol 2022; 28:653-663. [PMID: 35317427 PMCID: PMC8900545 DOI: 10.3748/wjg.v28.i6.653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/19/2021] [Accepted: 01/19/2022] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most frequently diagnosed tumor globally. In most cases, GC develops in a stepwise manner from chronic gastritis or atrophic gastritis (AG) to cancer. One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis. MicroRNAs (miRNAs) are small noncoding molecules that play an essential role in a variety of fundamental biological processes. However, clinical potential of miRNA profiling in the gastric cancerogenesis, especially in premalignant GC cases, remains unclear. AIM To evaluate the AG and GC tissue miRNomes and identify specific miRNAs' potential for clinical applications (e.g., non-invasive diagnostics). METHODS Study included a total of 125 subjects: Controls (CON), AG, and GC patients. All study subjects were recruited at the Departments of Surgery or Gastroenterology, Hospital of Lithuanian University of Health Sciences and divided into the profiling (n = 60) and validation (n = 65) cohorts. Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing (NGS). Based on NGS data, deregulated miRNAs hsa-miR-129-1-3p and hsa-miR-196a-5p were analyzed in plasma samples of independent cohort consisting of CON, AG, and GC patients. Expression level of hsa-miR-129-1-3p and hsa-miR-196a-5p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method. RESULTS Results of tissue analysis revealed 20 differentially expressed miRNAs in AG group compared to CON group, 129 deregulated miRNAs in GC compared to CON, and 99 altered miRNAs comparing GC and AG groups. Only 2 miRNAs (hsa-miR-129-1-3p and hsa-miR-196a-5p) were identified to be step-wise deregulated in healthy-premalignant-malignant sequence. Area under the curve (AUC)-receiver operating characteristic analysis revealed that expression level of hsa-miR-196a-5p is significant for discrimination of CON vs AG, CON vs GC and AG vs GC and resulted in AUCs: 88.0%, 93.1% and 66.3%, respectively. Compar-ing results in tissue and plasma samples, hsa-miR-129-1-3p was significantly down-regulated in GC compared to AG (P = 0.0021 and P = 0.024, tissue and plasma, respectively). Moreover, analysis revealed that hsa-miR-215-3p/5p and hsa-miR-934 were significantly deregulated in GC based on Helicobacter pylori (H. pylori) infection status [log2 fold change (FC) = -4.52, P-adjusted = 0.02; log2FC = -4.00, P-adjusted = 0.02; log2FC = 6.09, P-adjusted = 0.02, respectively]. CONCLUSION Comprehensive miRNome study provides evidence for gradual deregulation of hsa-miR-196a-5p and hsa-miR-129-1-3p in gastric carcinogenesis and found hsa-miR-215-3p/5p and hsa-miR-934 to be significantly deregulated in H. pylori carrying GC patients.
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Affiliation(s)
- Greta Varkalaite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Evelina Vaitkeviciute
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Ruta Inciuraite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Violeta Salteniene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Simonas Juzenas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Vytenis Petkevicius
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Rita Gudaityte
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Antanas Mickevicius
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg 39120, Germany
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Marcis Leja
- Institute of Clinical and Preventive Medicine & Faculty of Medicine, University of Latvia, Riga 1586, Latvia
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
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33
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Zhao P, Ma X, Cheng J, Chen H, Li L. Identification of the hub genes and transcription factor-miRNA axes involved in Helicobacter pylori-associated gastric cancer. Oncol Lett 2022; 23:89. [PMID: 35126731 PMCID: PMC8805177 DOI: 10.3892/ol.2022.13209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 11/26/2021] [Indexed: 12/03/2022] Open
Abstract
It has been previously reported that transcription factor-microRNA (TF-miRNA) axes play a significant role in the carcinogenesis of several types of malignant tumor. However, there is a lack of research into the differences in the mechanism of Helicobacter pylori (HP)-positive [HP(+)] and HP-negative [HP(−)] gastric cancer. The aim of the present study was to identify the hub genes and TF-miRNA axes, and to determine the potential mechanisms involved in HP-associated gastric cancer. HP-associated mRNA and miRNA data, as well as the corresponding clinical information, was downloaded from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) and DE miRNAs (DEMs) were then identified from the HP(+) and HP(−) cancer mRNA and miRNA datasets, respectively. Subsequently, gene set enrichment analysis and the protein-protein interaction (PPI) networks were investigated using the ClusterProfiler packages. Lastly, TF-miRNA-DEG networks were constructed using the miRWalk online tool. A total of 1,050 DEGs and 13 DEMs were identified from the normalized mRNA and miRNA expression datasets, respectively. In addition, 180 Gene Ontology terms and 30 Kyoto Encyclopedia of Genes and Genomes pathways were found to be enriched, while 6 hub genes were identified from the PPI analysis. Furthermore, 7 TF-miRNA interactions and 181 TF-miRNA-DEG axes were constructed using an integrated bioinformatics approach, while 2 TF-miRNA interactions (ZEB1-miRNA-144-3p and PAX2-miRNA-592) were confirmed using reverse transcription-quantitative PCR in samples from enrolled patients. Moreover, the ZEB1-miRNA-144-3p axis was further validated based on dual luciferase reporter assay results. In summary, an integrated bioinformatics approach was used to screen the significant molecular and regulatory axes, which may provide a novel direction to investigate the pathogenesis of gastric cancer associated with HP.
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Affiliation(s)
- Peng Zhao
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xianxiong Ma
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jiancheng Cheng
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Hengyu Chen
- Department of Breast and Thyroid Surgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570100, P.R. China.,Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Lei Li
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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34
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Gilani N, Arabi Belaghi R, Aftabi Y, Faramarzi E, Edgünlü T, Somi MH. Identifying Potential miRNA Biomarkers for Gastric Cancer Diagnosis Using Machine Learning Variable Selection Approach. Front Genet 2022; 12:779455. [PMID: 35082831 PMCID: PMC8785967 DOI: 10.3389/fgene.2021.779455] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/22/2021] [Indexed: 01/21/2023] Open
Abstract
Aim: This study aimed to accurately identification of potential miRNAs for gastric cancer (GC) diagnosis at the early stages of the disease. Methods: We used GSE106817 data with 2,566 miRNAs to train the machine learning models. We used the Boruta machine learning variable selection approach to identify the strong miRNAs associated with GC in the training sample. We then validated the prediction models in the independent sample GSE113486 data. Finally, an ontological analysis was done on identified miRNAs to eliciting the relevant relationships. Results: Of those 2,874 patients in the training the model, there were 115 (4%) patients with GC. Boruta identified 30 miRNAs as potential biomarkers for GC diagnosis and hsa-miR-1343-3p was at the highest ranking. All of the machine learning algorithms showed that using hsa-miR-1343-3p as a biomarker, GC can be predicted with very high precision (AUC; 100%, sensitivity; 100%, specificity; 100% ROC; 100%, Kappa; 100) using with the cut-off point of 8.2 for hsa-miR-1343-3p. Also, ontological analysis of 30 identified miRNAs approved their strong relationship with cancer associated genes and molecular events. Conclusion: The hsa-miR-1343-3p could be introduced as a valuable target for studies on the GC diagnosis using reliable biomarkers.
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Affiliation(s)
- Neda Gilani
- Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Arabi Belaghi
- Department of Mathematics, Uppsala University, Uppsala, Sweden
- Department of Statistics, Faculty of Mathematical Science, University of Tabriz, Tabriz, Iran
| | - Younes Aftabi
- Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elnaz Faramarzi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tuba Edgünlü
- Department of Medical Biology, Faculty of Medicine, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Zheng L, Wu Y, Shen L, Liang X, Yang Z, Li S, Li T, Shang W, Shao W, Wang Y, Liu F, Ma L, Jia J. Mechanisms of JARID1B Up-Regulation and Its Role in Helicobacter pylori-Induced Gastric Carcinogenesis. Front Oncol 2021; 11:757497. [PMID: 34778074 PMCID: PMC8581301 DOI: 10.3389/fonc.2021.757497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/07/2021] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.
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Affiliation(s)
- Lixin Zheng
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yujiao Wu
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Li Shen
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xiuming Liang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Zongcheng Yang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Shuyan Li
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Tongyu Li
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wenjing Shang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wei Shao
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yue Wang
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Fen Liu
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Lin Ma
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jihui Jia
- Key Laboratory of Experimental Teratology, School of Basic Medical Sciences, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Infection and Immunology, School of Basic Medical Sciences, Shandong University, Jinan, China
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36
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Boubrik F, Belmouden A, Kadmiri NE. Potential Non-invasive Biomarkers of Helicobacter pylori-Associated Gastric Cancer. J Gastrointest Cancer 2021; 53:1113-1120. [PMID: 34767179 DOI: 10.1007/s12029-021-00734-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastric cancer (GC) remains the fifth most common incident cancer with the highest incidence in East Asian countries and the third leading cause of cancer death worldwide. The causal association between non-cardia GC and Helicobacter pylori (H. pylori) has been firmly documented by clinical and epidemiological studies. According to the guidelines for diagnosis and treatment of H. pylori infection, eradication therapy is strongly recommended. Early detection of GC is critical and can save lives through rapid technological advancement. At present, endoscopy remains the most efficient technique. However, it is invasive and costs highly. METHODS An extensive bibliographic search was performed via PubMed/Medline, Web of Science, and EBSCO host databases to select studies conducted within the past 8 years. Forty-six relevant analyses were encompassed in this review. RESULTS Several non-invasive candidate biomarkers associated with H. pylori, divided into virulence markers, transcriptome markers, genomic markers, and inflammatory markers, have been shown to be potential predictors of GC at an early stage. CONCLUSION The discovery of non-invasive biomarkers offers new perspectives for screening, early detection, and monitoring of individuals at risk.
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Affiliation(s)
- Fatima Boubrik
- Laboratory of Cell Biology and Molecular Genetics, Faculty of Science, Ibn Zohr University, Agadir, Morocco
| | - Ahmed Belmouden
- Laboratory of Cell Biology and Molecular Genetics, Faculty of Science, Ibn Zohr University, Agadir, Morocco
| | - Nadia El Kadmiri
- Molecular Engineering, Valorization and Environment Team, Polydisciplinary Faculty of Taroudant, Ibn Zohr University, Hay El Mohammadi (Lastah), Taroudannt, BP: 271, 83000, Morocco.
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Pehlevan Özel H, Dinç T, Tiryaki RS, Keşküş AG, Konu Ö, Kayilioğlu SI, Coşkun F. Targeted MicroRNA Profiling in Gastric Cancer with Clinical Assessement. Balkan J Med Genet 2021; 24:55-64. [PMID: 36249523 PMCID: PMC9524170 DOI: 10.2478/bjmg-2021-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Although several microRNAs (miRNAs) have been associated with gastric cancer there is still the need for identification of stable and validated biomarkers. The purpose of this study was to determine the alterations of a specific set of miRNA levels in gastric adenocarcinoma tissues to identify and validate gastric cancer-specific miRNAs using paired normal and tumor samples in an independent patient cohort. Gastric adenocarcinoma and normal stomach tissue samples of 20 patients who underwent surgery for gastric cancer were studied. The miRNA expression profiling was performed for eight miRNAs in a total of 40 tissue samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Six out of these eight miRNAs, namely, miR-375-3p, hsamiR-129-5p, miR-196a-5p, miR-376c-3p, miR-34c-5p and miR-767-5p, were significantly underexpressed in malignant tissues of our cohort. Furthermore, the expression of miR-662 although not significantly different between normal and tumor tissues, was inversely associated with age (r = -0.440, p = 0.049). The levels of miR-129-3p and miR34c-5p were correlated with an increase in the number of metastatic lymph nodes (r = 0.470, p = 0.036; r = 0.510, p = 0.020), while and miR-376c-3p levels were negatively associated with smoking (p = 0.043). In addition, we found that the variability of miRNA expression in cancerous tissues was lower than that in normal tissues. Alterations in miRNA expression in gastric adenocarcinoma tissues in comparison to healthy tissues of each individual serves for identification of consistent biomarkers that can be used for development of diagnostic tools for gastric cancer.
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Affiliation(s)
- H Pehlevan Özel
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
| | - T Dinç
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
| | - RS Tiryaki
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - AG Keşküş
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Ö Konu
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - SI Kayilioğlu
- Department of General Surgery, Sıtkı Koçman University, Muğla, Turkey
| | - F Coşkun
- Department of General Surgery, Health Sciences University, Ankara City Hospital, Ankara, Turkey
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Chivu-Economescu M, Necula L, Matei L, Dragu D, Bleotu C, Diaconu CC. Clinical Applications of Liquid Biopsy in Gastric Cancer. Front Med (Lausanne) 2021; 8:749250. [PMID: 34651002 PMCID: PMC8505538 DOI: 10.3389/fmed.2021.749250] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 08/31/2021] [Indexed: 02/05/2023] Open
Abstract
Liquid biopsy represents an exciting new area in the field of cancer diagnosis and management, offering a less invasive and more convenient approach to obtain a time-point image of the tumor burden and its genomic profile. Samples collected from several body fluids, mostly blood, can be used to gain access to circulating tumor cells and DNA, non-coding RNAs, microRNAs, and exosomes, at any moment, offering a dynamic picture of the tumor. For patients with GC, the use of blood-based biopsies may be particularly beneficial since tissue biopsies are difficult to obtain and cause real distress to the patient. With advantages such as repeatability and minimal invasion, it is no wonder that the field of liquid biopsy has received tremendous attention. However, the abundance of studies, involving a wide range of assays with different principles, prevented for the moment the reproducibility of the results and therefore the translation into the clinic of liquid biopsy. In this review, we present the latest technical development and data on circulating biomarkers available through liquid biopsy in gastric cancer with an emphasis on their clinical utility in areas such as cancer screening, prognostic stratification, and therapeutic management.
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Laura Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Denisa Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
| | - Carmen C. Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
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Varkalaite G, Forster M, Franke A, Kupcinskas J, Skieceviciene J. Liquid Biopsy in Gastric Cancer: Analysis of Somatic Cancer Tissue Mutations in Plasma Cell-Free DNA for Predicting Disease State and Patient Survival. Clin Transl Gastroenterol 2021; 12:e00403. [PMID: 34644276 PMCID: PMC8462609 DOI: 10.14309/ctg.0000000000000403] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/05/2021] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Gastric cancer (GC) diagnosis in late stages and high mortality rates are the main issues that require new noninvasive molecular tools. We aimed to assess somatic mutational profiles in GC tissue and plasma cell-free DNA (cfDNA), evaluate their concordance rate, and analyze the role of multilayer molecular profiling to predict disease state and prognosis. METHODS Treatment-naive GC patient group (n = 29) was selected. Whole exome sequencing (WES) of GC tissue was performed, and a unique 38-gene panel for deep targeted sequencing of plasma cfDNA was developed. Oncoproteins were measured by enzyme-linked immunosorbent assay, and other variables such as tumor mutational burden and microsatellite instability were evaluated using WES data. RESULTS The yield of cfDNA was increased 43.6-fold; the integrity of fragments was decreased in GC compared with controls. WES analysis of cancerous tissue and plasma cfDNA (targeted sequencing) mutational profiles revealed 47.8% concordance. The increased quantity of GC tissue-derived alterations detected in cfDNA was associated with worse patients' survival. Analysis of importance of multilayer variables and receiver operating characteristic curve showed that combination of 2 analytes: (i) quantity of tissue matching alterations and (ii) presence of any somatic alteration in plasma cfDNA resulted in area under curve 0.744 when discriminating patients with or without distant metastasis. Furthermore, cfDNA sequence alterations derived from tumor tissue were detected in patients who had even relatively small GC tumors (T1-T2). DISCUSSION Our results indicate that quantitative and qualitative cfDNA mutational profile analysis is a promising tool for evaluating GC disease status or poorer prognosis.
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Affiliation(s)
- Greta Varkalaite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
| | - Michael Forster
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;
| | - Juozas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
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Chen S, Wu H, Zhu L, Jiang M, Wei S, Luo J, Liu A. MiR-199b-5p Promotes Gastric Cancer Progression by Regulating HHIP Expression. Front Oncol 2021; 11:728393. [PMID: 34532291 PMCID: PMC8438221 DOI: 10.3389/fonc.2021.728393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 12/29/2022] Open
Abstract
Objectives Gastric cancer (GC) is one of the most common malignant tumors. More and more evidences support the role of microRNAs (miRNAs) in tumor progression. However, the role of miRNAs in human GC remains largely unknown. Methods Based on the published gastric cancer expression profile data, combined with bioinformatics analysis, potential miRNAs in the process of GC were screened. The expression of miR-199b-5p in GC cells and patients’ plasma was detected by RT-PCR. The effects of miR-199b-5p on GC in vitro were detected by EdU proliferation assay, colony formation assay, Transwell assay and wound healing assay. Western blot was used to detect epithelial-mesenchymal transition (EMT) related proteins. The subcutaneous tumorigenesis model and metastatic tumor model of mice were used to study its effect in vivo. Bioinformatics and Dual luciferase reporter assay were used to verify the effect of miR-199b-5p and its target gene. Results Through bioinformatics analysis, we screened a novel miRNA miR-199b-5p that was significantly up-regulated in GC tissue and associated with poor prognosis of GC patients. RT-PCR results showed that its expression was also up-regulated in GC cell lines and patients’ plasma. MiR-199b-5p can significantly promote GC cell proliferation and migration in vitro and in vivo. Western blot showed that miR-199b-5p could promote the EMT process of GC. HHIP has been proved to be a target of miR-199b-5p, and the recovery of HHIP can weaken the effect of miR-199b-5p. Conclusion MiR-199b-5p may play an oncogene role in GC by targeting HHIP, suggesting that miR-199b-5p may be a potential therapeutic target for GC.
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Affiliation(s)
- Songda Chen
- Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Huijie Wu
- Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lingyu Zhu
- Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mengjie Jiang
- Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shuli Wei
- Department of Gastroenterology, The 10th Affiliated Hospital of Guangxi Medical University, Qinzhou, China
| | - Jinhua Luo
- Department of Gastroenterology, The 10th Affiliated Hospital of Guangxi Medical University, Qinzhou, China
| | - Aiqun Liu
- Department of Endoscopy, Guangxi Medical University Cancer Hospital, Nanning, China
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Modern possibilities and prospects of early diagnosis of stomach cancer. ACTA BIOMEDICA SCIENTIFICA 2021. [DOI: 10.29413/abs.2021-6.3.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Xu WS, Ke F, Xu Y, Zheng Y. LINC00963 regulates gastric cancer cell proliferation, migration, and invasion through miR-146a-5p/NFE2L1 axis. Shijie Huaren Xiaohua Zazhi 2021; 29:690-700. [DOI: 10.11569/wcjd.v29.i13.690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Long intergenic non-coding RNA 00963 (LINC00963) is up-regulated in tumors, but the function and mechanism of LINC00963 in gastric cancer have not been elucidated. It was predicted using Starbase that microRNA (miR)-146a-5p may be the target gene of LINC00963, and nuclear factor erythroid-2 like 1 (NFE2L1) may be the target gene of miR-146a-5p. We hypothesized that LINC00963 may affect the proliferation, migration and invasion of gastric cancer cells by regulating the miR-146a-5p/NFE2L1 axis.
AIM To explore the effect of LINC00963 on the proliferation, migration, and invasion of gastric cancer cells and the underlying molecular mechanism.
METHODS The cancer tissues and adjacent tissues of 42 patients with gastric cancer were collected, and real-time quantitative PCR (RT-qPCR) was used to detect the expression level of LINC00963 in these tissues. RT-qPCR was also used to detect the expression of LINC00963, miR-146a-5p, and NFE2L1 mRNA in gastric cancer cell lines SNU-1, AGS, and HS-746T. SNU-1 cells were then divided into a normal control group (NC) group, si-LINC00963 group, si-NFE2L1 group, si-NC group, miR-146a-5p group, miR-NC group, si-LINC00963 + pcDNA-NC Group, and si-LINC00963 + pcDNA-NFE2L1 group; CCK-8 was used to detect cell viability, Transwell assay was used to detect cell migration and invasion, and dual luciferase reporter assay was used to detect the targeting relationship among LINC00963, miR-146a-5p, and NFE2L1.
RESULTS The expression level of LINC00963 in gastric cancer tissues and gastric cancer cell lines SNU-1, AGS, and HS-746T was increased, the expression level of miR-146a-5p was decreased in gastric cancer cell lines, and the expression level of NFE2L1 mRNA was increased (P < 0.05). With low expression of LINC00963 and NFE2L1 or high expression of miR-146a-5p, the viability of SNU-1 cells was decreased, and the ability of cell migration and invasion was decreased (P < 0.05). High expression of NFE2L1 can reverse the effect of low expression of LINC00963 on SNU-1 cells. LINC00963 targets and regulates miR-146a-5p, while miR-146a-5p targets and regulates NFE2L1.
CONCLUSION Low expression of LINC00963 inhibits the proliferation, migration, and invasion of gastric cancer cells by regulating the miR-146a-5p/NFE2L1 axis.
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Affiliation(s)
- Wan-Su Xu
- Department of Oncology Radiotherapy, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
| | - Fei Ke
- Department of Pathology, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
| | - Yi Xu
- Sterilized Supplying Center, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
| | - Yi Zheng
- Sterilized Supplying Center, Quzhou People's Hospital, Quzhou 324000, Zhejiang Province, China
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Jiang H, Liu Y, Hu K, Xia Y, Liang L, Zhu X, Cheng X. MiRNA-339 targets and regulates ZNF689 to inhibit the proliferation and invasion of gastric cancer cells. Transl Cancer Res 2021; 10:3516-3526. [PMID: 35116655 PMCID: PMC8799122 DOI: 10.21037/tcr-21-994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/02/2021] [Indexed: 11/06/2022]
Abstract
BACKGROUND Gastric cancer (GC) is the most common malignant tumor of the digestive system, and its mortality rate ranks first among malignant tumors. However, the pathogenesis of GC has not yet been fully elucidated. This study found that microRNA (miRNA)-339 is abnormally expressed in GC tissues. However, the role and molecular mechanism of miRNA-339 in the occurrence and development of GC are still unclear. METHODS Fluorescence quantitative polymerase chain reaction (qPCR) was used to detect the expression level of miRNA-339 in GC tissues and adjacent tissues and analyze the correlation with the clinicopathological characteristics of GC patients. Cell counting kit-8 (CCK-8) and Transwell experiments detected the effect of overexpression of miRNA-339 on the proliferation, invasion, and migration of GC cells. The luciferase reporter gene detected the downstream target molecules regulated by miRNA-339, and western blot was employed to detect the effect of overexpression of miRNA-339 on the expression of ZNF689. RESULTS The results of fluorescence qPCR showed that miRNA-339 was less expressed in GC tissues compared with adjacent tissues, and it was correlated with the patient's clinical tumor, node, metastasis (TNM) grade and lymph node metastasis. Cell function experiments showed that overexpression of miRNA-339 can significantly inhibit the proliferation, invasion, and migration of GC cells. The luciferase reporter gene showed that miRNA-339 can bind to the 3'-UTR region of ZNF689, and overexpression of miRNA-339 can significantly inhibit the expression of ZNF689 in GC cells. Overexpression of ZNF689 can significantly block the ability of overexpression of miRNA-339 to inhibit the proliferation and migration of GC cells. CONCLUSIONS miRNA-339 inhibits the proliferation and invasion of GC cells through targeted regulation of the expression of ZNF689. In addition, the expression level of miRNA-339 can be used as a biomarker for the prognosis of GC.
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Affiliation(s)
- Houxiang Jiang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital Wannan Medical College) Wuhu, China
| | - Yinhua Liu
- Department of Pathology, the First Affiliated Hospital of Wannan Medical College (YIjishan Hospital of Wanna Medical College), Wuhu, China
| | - Kaifeng Hu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital Wannan Medical College) Wuhu, China
| | - Yabin Xia
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital Wannan Medical College) Wuhu, China
| | - Linhu Liang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital Wannan Medical College) Wuhu, China
| | - Xiaoli Zhu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital Wannan Medical College) Wuhu, China
| | - Xianfeng Cheng
- Department of Laboratory Medicine, Dermatology Hospital of Chinese Academy of Medical Sciences (Institute), Nanjing, China
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Jonaitis P, Kupcinskas L, Kupcinskas J. Molecular Alterations in Gastric Intestinal Metaplasia. Int J Mol Sci 2021; 22:ijms22115758. [PMID: 34071181 PMCID: PMC8199079 DOI: 10.3390/ijms22115758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
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Bure IV, Nemtsova MV. Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected. Int J Mol Sci 2021; 22:ijms22115683. [PMID: 34073603 PMCID: PMC8199097 DOI: 10.3390/ijms22115683] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Despite recent progress, gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Aberrant DNA methylation pattern and deregulation of noncoding RNA expression appear in the early stages of gastric cancer. Numerous investigations have confirmed their significant role in gastric cancer tumorigenesis and their high potential as diagnostic and prognostic biomarkers. Currently, it is clear that these epigenetic regulators do not work alone but interact with each other, generating a complex network. The aim of our review was to summarize the current knowledge of this interaction in gastric cancer and estimate its clinical potential for the diagnosis, prognosis, and treatment of the disease.
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Affiliation(s)
- Irina V. Bure
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Correspondence: ; Tel.: +49-915-069-2721
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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Mahjoor M, Afkhami H, Mollaei M, Nasr A, Shahriary S, Khorrami S. MicroRNA-30c delivered by bone marrow-mesenchymal stem cells induced apoptosis and diminished cell invasion in U-251 glioblastoma cell line. Life Sci 2021; 279:119643. [PMID: 34048811 DOI: 10.1016/j.lfs.2021.119643] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/10/2021] [Accepted: 05/14/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Glioblastoma multiform (GBM) is the most belligerent and prevalent brain malignancy among adults. Due to the blood-brain barrier (BBB), drug administration is confronted by massive challenges, making resectional surgery the only treatment pipeline. MicroRNAs have recently absorbed the attention of studies for correlating with the progression of various malignancies. miR-30c has been reported to play a role in cell proliferation, metabolism, and apoptosis process. For instance, miR-30c has been reported to regulate apoptosis through the TNF-related apoptosis-inducing ligand (TRAIL). miR-30c also targets IL-6, which further induces apoptosis. Besides, miR-30c inhibits glioma proliferation and its migratory ability. Besides, the overexpression of miR-30c arrested cells at G0 as well as dampening their migration and invasion. However, it has been shown that the expression level of miR-30c was low in glioma. MSCs can migrate toward tumor cells which is called tumor-tropism, in which they are capable of delivering engineered miR-30c based on gap junction and non-intimacy mechanisms. MATERIAL AND METHODS MiR-30c was cloned into pCDH-CMV-MCS-EF1-copGFP vector utilizing XbaI and EcoRI in order to construct pCDH-miR-30c. Then psPAX2, pMD2.G, and pCDH-miR-30c were co-transfected into Hek-293T to yield lenti-miR-30c virus particles. Next, bone marrow-mesenchymal stem cells (BM-MSCs) were Transduced with lenti-miR-30c. Thereafter, we co-cultured U-251 cell line with BM-MCSs-miR-30c and evaluated the apoptosis rate and the relative expression level of IL-6, Klf4, Sox2, c-Myc, and Oct4 using Real-Time PCR and flow cytometry. RESULTS Wound healing assays represented low migratory ability in U-251 cells treated with BM-MSCs-miR-30c. Plus, apoptosis assay using Annexin V/7AAD showed an increased number of apoptotic U-251 cells following the treatment. miR-30 targeted IL-6 and induced apoptosis. It also impacted on the self-renewal and the anti-apoptotic cluster of genes, namely Klf4, Sox2, c-Myc, and Oct4, to induce apoptosis and dwindle the migration and invasion.
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Affiliation(s)
- Mohamad Mahjoor
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Department of Medical Microbiology, Faculty of Medicine, Shahed University of Medical Sciences, Tehran, Iran
| | - Mojtaba Mollaei
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Atieh Nasr
- Bachelor Student of Biochemistry, Department of Biochemistry, Islamic Azad University of Najafabad, Esfahan, Iran
| | - Shamin Shahriary
- Bachelor Student of Microbiology, Department of Microbiology, Islamic Azad University, North Tehran Branch, Tehran, Iran
| | - Samaneh Khorrami
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Abstract
Gastric cancer (GC) is one of the most common malignant tumors. The mechanism of how GC develops is vague, and therapies are inefficient. The function of microRNAs (miRNAs) in tumorigenesis has attracted the attention from many scientists. During the development of GC, miRNAs function in the regulation of different phenotypes, such as proliferation, apoptosis, invasion and metastasis, drug sensitivity and resistance, and stem-cell-like properties. MiRNAs were evaluated for use in diagnostic and prognostic predictions and exhibited considerable accuracy. Although many problems exist for the application of therapy, current studies showed the antitumor effects of miRNAs. This paper reviews recent advances in miRNA mechanisms in the development of GC and the potential use of miRNAs in the diagnosis and treatment of GC.
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So JBY, Kapoor R, Zhu F, Koh C, Zhou L, Zou R, Tang YC, Goo PCK, Rha SY, Chung HC, Yoong J, Yap CT, Rao J, Chia CK, Tsao S, Shabbir A, Lee J, Lam KP, Hartman M, Yong WP, Too HP, Yeoh KG. Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population. Gut 2021; 70:829-837. [PMID: 33028667 PMCID: PMC8040159 DOI: 10.1136/gutjnl-2020-322065] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/08/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE An unmet need exists for a non-invasive biomarker assay to aid gastric cancer diagnosis. We aimed to develop a serum microRNA (miRNA) panel for identifying patients with all stages of gastric cancer from a high-risk population. DESIGN We conducted a three-phase, multicentre study comprising 5248 subjects from Singapore and Korea. Biomarker discovery and verification phases were done through comprehensive serum miRNA profiling and multivariant analysis of 578 miRNA candidates in retrospective cohorts of 682 subjects. A clinical assay was developed and validated in a prospective cohort of 4566 symptomatic subjects who underwent endoscopy. Assay performance was confirmed with histological diagnosis and compared with Helicobacter pylori (HP) serology, serum pepsinogens (PGs), 'ABC' method, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9). Cost-effectiveness was analysed using a Markov decision model. RESULTS We developed a clinical assay for detection of gastric cancer based on a 12-miRNA biomarker panel. The 12-miRNA panel had area under the curve (AUC)=0.93 (95% CI 0.90 to 0.95) and AUC=0.92 (95% CI 0.88 to 0.96) in the discovery and verification cohorts, respectively. In the prospective study, overall sensitivity was 87.0% (95% CI 79.4% to 92.5%) at specificity of 68.4% (95% CI 67.0% to 69.8%). AUC was 0.848 (95% CI 0.81 to 0.88), higher than HP serology (0.635), PG 1/2 ratio (0.641), PG index (0.576), ABC method (0.647), CEA (0.576) and CA19-9 (0.595). The number needed to screen is 489 annually. It is cost-effective for mass screening relative to current practice (incremental cost-effectiveness ratio=US$44 531/quality-of-life year). CONCLUSION We developed and validated a serum 12-miRNA biomarker assay, which may be a cost-effective risk assessment for gastric cancer. TRIAL REGISTRATION NUMBER This study is registered with ClinicalTrials.gov (Registration number: NCT04329299).
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Affiliation(s)
- Jimmy Bok Yan So
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,Division of Surgical Oncology, National University Cancer Institute, Singapore,Department of Surgery, National University Hospital, Singapore
| | - Ritika Kapoor
- Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - Feng Zhu
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore
| | - Calvin Koh
- Department of Gastroenterology and Hepatology, National University Hospital, Singapore
| | - Lihan Zhou
- Department of Research and Development, MiRXES Lab, Singapore
| | - Ruiyang Zou
- Department of Research and Development, MiRXES Lab, Singapore
| | - Yew Chung Tang
- Department of Research and Development, MiRXES Lab, Singapore
| | - Patrick C K Goo
- Diagnostics Development Hub, Accelerate Technologies Pte Ltd, Agency for Science Technology and Research, Singapore
| | - Sun Young Rha
- Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Cheol Chung
- Yonsei Cancer Center, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joanne Yoong
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Celestial T Yap
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jaideepraj Rao
- Department of Surgery, Tan Tock Seng Hospital, Singapore
| | - Chung-King Chia
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore
| | - Stephen Tsao
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore
| | - Asim Shabbir
- Department of Surgery, National University Hospital, Singapore
| | - Jonathan Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore,Department of Gastroenterology and Hepatology, National University Hospital, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science Technology and Research, Singapore
| | - Mikael Hartman
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore
| | - Heng-Phon Too
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Khay-Guan Yeoh
- Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore .,Department of Gastroenterology and Hepatology, National University Hospital, Singapore.,Singapore Gastric Cancer Consortium, Singapore
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Vasapolli R, Venerito M, Schirrmeister W, Thon C, Weigt J, Wex T, Malfertheiner P, Link A. Inflammatory microRNAs in gastric mucosa are modulated by Helicobacter pylori infection and proton-pump inhibitors but not by aspirin or NSAIDs. PLoS One 2021; 16:e0249282. [PMID: 33857171 PMCID: PMC8049315 DOI: 10.1371/journal.pone.0249282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/15/2021] [Indexed: 12/21/2022] Open
Abstract
Gastric carcinogenesis is associated with alterations of microRNAs (miRNAs) and reversal of these alterations may be a crucial element in cancer prevention. Here we evaluate the influence of H. pylori eradication, low-dose aspirin (LDA), non-steroidal anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors (PPI) on modification of inflammatory mucosal miRNAs miR-155 and miR-223 in Helicobacter pylori-infected and non-infected subjects. The study was performed in two parts: 1) interventional study in 20 healthy subjects with and without H. pylori infection or following eradication (each n = 10) where LDA (100 mg) was given daily for 7 days; 2) prospective case-control observational study (n = 188). MiR-155 and miR-223 expression was strongly linked to H. pylori-infection and in short-term view showed a trend for reversal after eradication. Daily LDA as well as regular NSAIDs showed no influence on miRNAs expression both in healthy subjects and patients, while regular PPI intake was associated with lower miR-155 expression in antrum of patients with chronic gastritis independent of density of neutrophils and mononuclear infiltrate. In summary, PPI but not LDA or NSAIDs were associated with modification of inflammatory miRNAs miR-155 and miR-223 in an H. pylori dependent manner. The functional role of inflammatory miR-155 and miR-223 in understanding of H. pylori-related diseases needs further evaluation.
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Affiliation(s)
- Riccardo Vasapolli
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
- Department of Internal Medicine II, Hospital of the Ludwig Maximilians University of Munich, Munich, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Wiebke Schirrmeister
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Jochen Weigt
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
- Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
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50
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Zhang H, Fu T, Zhang C. MicroRNA-1249 Targets G Protein Subunit Alpha 11 and Facilitates Gastric Cancer Cell Proliferation, Motility and Represses Cell Apoptosis. Onco Targets Ther 2021; 14:1249-1259. [PMID: 33658793 PMCID: PMC7917321 DOI: 10.2147/ott.s272599] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 01/22/2021] [Indexed: 12/27/2022] Open
Abstract
Aim The purpose of our study was to investigate the effects of miR-1249 in gastric cancer. Methods By analyzing the data obtained from TCGA database, the expression and prognosis of miR-1249 in gastric cancer patients were analyzed. Then, CCK8, colony forming and transwell assays were used to test cell proliferation and motility. The cell apoptosis was detected by flow cytometry. The Pearson correlation coefficient analyzed was applied to analyze the correlation between GNA11 and miR-1249. qRT-PCR and Western blotting assays were employed to detect the mRNA and protein levels. Results We discovered that miR-1249 was highly expressed and was associated with a worse prognosis in gastric cancer patients. Besides, miR-1249 was up-regulated in gastric cancer cell lines (AGS, MKN45 and SNU1). More interestingly, miR-1249 exerted facilitating impacts on gastric cancer cell proliferation and motility, whereas miR-1249 acted as a suppressing effect on gastric cancer apoptosis. G protein subunit alpha 11 (GNA11) was a target gene of miR-1249 and was negatively correlated with miR-1249. Furthermore, GNA11 was negatively regulated by miR-1249. Additionally, GNA11 was lowly expressed in gastric cancer tissues and cell lines, as well as low GNA11 expression, was related to poor overall survival results in gastric cancer patients. The promoting influences of miR-1249 over-expression on AGS cell proliferation and motility was rescued by GNA11 over-expression, which might be achieved by regulating PI3K/AKT/mTOR signalling pathway. Conclusion Above all, we concluded that miR-1249 was concerned with the progression of gastric cancer through regulating GNA11, suggesting that miR-1249 and GNA11 might serve as predictive biomarkers for gastric cancer therapy.
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Affiliation(s)
- Hongzhu Zhang
- Department of Gastroenterology, Jinan Jigang Hospital, Jinan, Shandong, 250101, People's Republic of China
| | - Tingting Fu
- Department of Gastroenterology, Jinan Jigang Hospital, Jinan, Shandong, 250101, People's Republic of China
| | - Cuiping Zhang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People's Republic of China
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